Many natural products, usually bacterial metabolites, feature a macrolide fused to a monocyclic benzenoid matrix, bearing a resorcinol-like substitution pattern. Not infrequently, the resorcinol moiety carries additional functionality, resulting in higher levels of oxidation. Natural products in this family (cf. inter alia radicicol (Delmotte, P.; Delmotte-Plaquee, J. Nature 1953, 171, 344; incorporated herein by reference), LL-Z-1640s (McGahren, W. J. J. Org. Chem. 1978, 43, 2339–2343; which is incorporated herein by reference), monocillins (Ayer, W. A.; Lee, S. P.; Tsuneda, A.; Hiratsuka, Y. Can. J. Microb. 1980, 26, 766–773; incorporated herein by reference), nordinone (Ayer, W. A.; Pena-Rodriguez, L. Phytochemistry 1987, 26, 1353–1355; incorporated herein by reference) and zearelenone (Sugawara, F.; Kim, K. W.; Kobayashi, K.; Uzawa, J.; Yoshida, S.; Murofushi, N.; Takahashi, N.; Strobel, G. A. Phytochemistry 1992, 31, 1987–1990; incorporated herein by reference) possess potentially exploitable patterns of antitumor, antibiotic, and antimalarial activity.
Radicicol (Delmotte et al. Nature 1953, 171, 344; Ayer et al. Canad. J. Microbiol. 1980, 26, 766) (1) and monocillin I (Ayer et al. Canad. J. Microbiol. 1980, 26, 766) (2) are resorcylic macrolides which can both be isolated from Monocillium nordinii (Ayer et al. Canad. J. Microbiol. 1980, 26, 766) (FIG. 1). While the skeletal structure of radicicol was determined in 1964, (McCapra et al. Tetrahedron Lett. 1964, 869; Mirrington et al. Tetrahedron Lett. 1964, 365) its relative and absolute stereochemical configuration was not unambiguously established until 1987 (Cutler et al. Agric. Biol. Chem. 1987, 51, 3331). The structure of monocillin I was confirmed by its direct conversion into radicicol. Affirmation of these structures was achieved by their only total synthesis through the efforts of Lett and Lampilas (Lampilas et al. Tetrahedron Lett. 1992, 33, 773 and 777).
Both radicicol (1) and monocillin I (2) (see FIG. 1) exhibit a variety of antifungal and antibiotic properties not shared by other members of this class of natural products. Recently, the antitumor properties of radicicol have come into focus as its ability to suppress the transformed phenotype caused by various oncogenes such as src, ras, and raf has been linked to its tight binding (20 nM) and inhibition of the Hsp90 molecular chaperone (Roe et al. J. Med. Chem. 1999, 42, 260–266). This ‘anti-chaperone’ activity may stimulate depletion of oncogenic proteins, and could therefore be of clinical interest. Specifically, occupancy of the ATP binding pocket of Hsp90 is believed to lead to the degradation in the proteasome of a subset of proteins involved in signal transduction that require Hsp90 for conformational maturation (see, Schneider et al. Proc. Natl. Acad. Sci. USA 93: 14536–14541, 1996; Mimnaugh et al. J. Biol. Chem. 271: 22796–22801, 1996; Whitesell et al. Mol. Endocrinol. 10: 705–712, 1996). These proteins include the HER and insulin receptor families of tyrosine kinases, Raf-1 serine kinase and steroid receptors to name a few. Downregulation of any of these would be expected to have positive antiproliferative effects, so that Hsp90 is an attractive target for the development of antitumor drugs.
More recently, five new 14-membered resorcyclic macrolides, termed aigailomycins A–E, were isolated from the marine mangrove fungus Aigialus parvus BCC5311 (Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561–1566; incorporated herein by reference). Among the aigailomycins, aigailomycin D exhibits potent antimalarial activity (IC50: 6.6 μg/mL against P. falciparum) and antitumor activity (IC50: 3.0 μg/mL against KB cells) (Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561–1566; incorporated herein by reference).
The demonstrated ability of radicicol to bind to and inhibit the activity of Hsp90 has generated an interest in further exploring the biological and pharmacological activity of radicicol and analogues thereof. Significantly, to date, only one synthesis of radicicol itself has been recorded (Lampilas et al. Tetrahedron Lett. 1992, 33, 773 and 777). Other groups have accessed a variety of analogues from the natural product itself (see, U.S. Pat. No. 5,650,430; U.S. Pat. No. 5,731,343; U.S. Pat. No. 6,239,168; U.S. Pat. No. 5,977,165; and U.S. Pat. No. 5,597,846; each of which is incorporated herein by reference), but have been limited in the range of analogues that can be generated. Thus, there remains a need to develop a practical synthesis of radicicol and other resorcyclic macrolides to generate novel analogs and conjugates to explore novel biological and pharmacological activities, and to improve the stability and therapeutic efficacy of radicicol, monocillin, and aigialomycins in the treatment of cancer.